Embed Size (px)
Citation preview
An Investigator‟s Perspective
Brendan M Buckley M.D. D.Phil. FRCPI
Clinical Professor of Medicine and Pharmacology
European Centre for Clinical Trials in Rare Diseases
University College Cork, Ireland
Firecrest Clinical
• Established in 2001 – Ireland & USA
• Over 160 studies across 70 countries
• Experience across all therapeutic areas in Phase II, III and IV trials
• Developed „by Investigators for Investigators‟
The Clinical Development Process 1
Under tight control of Sponsor:
Drug discovery
Non-clinical development
Phase 1
Phase 2 (maybe)
Ensured by:
Hiring policy
Training
Tight supervision
S.O.Ps
Performance review
Accountability
Firing policy
$200 million
ballpark
The Sponsor Struggles to Control:
• Phase 2 (maybe)
• Phase 3
• Phase 4
• PMS
Problems in Control
Not Investigators‟ core business
• Motivation of Investigators
• Training of Investigators
• Supervision of sites
• “Don’t upset the K.O.L.s !”
• Turnover of staff
$500 million
ballpark
The Clinical Development Process 2
A Cynical View?
First, spend $200 million on carefully nurturing a new drug from its discovery
through non-clinical development, then hand it over to a bunch of semi-
amateurs AND struggle to try to ensure that it all works out.
The Clinical Development Process
Objectives in the Clinical Trial Process
Decrease cycle times
Maintain (and preferably improve) quality
Ensure that trial results fairly reflect the drug’s characteristics
Control costs
“Within the R&D process, clinical trials form the largest single cost center for new
drug development.”
Global Information, Inc. „Optimizing the Clinical Trial Process: Strategies to Reduce Costs and Increase Quality.‟
Challenges in the Clinical Trial Pathway
80% of clinical trials fail to finish on time.Paraxel. Pharmaceutical R&D Statistical Sourcebook, 2001
25% of Informed Consents are inadequate or missing.Bohaychuck W, Bell G. Conducting GCP Compliant Clinical Research, Wiley
Delays in attaining MA result in a cost to companies of as much as $1million a day in unrealised sales.
Kermani F, Findlay G (2000). The Pharmaceutical R&D Compendium.
Only 50% of successful Phase II trials meet their Phase III endpointsRobert O‟Neill, FDA, speaking at DIA EuroMeeting, Paris 2006
30% of Phase III trial failures are likely due to problems in execution
The Classical Response
“We need to hold an Investigator Meeting”
Conservatively… $2000 per participant within the US !
Polling Question
What is the most likely outcome of an IM held before
trial commencement?
1. Attendees learn all they need to know about the trial?
2. Sponsor and CRO staff will network well with Investigators?
3. We get to visit interesting places?
4. Everyone‟s risk of DVT is increased?
5. It‟s a good use of time and resources?
Why hold Investigator Meetings?
….. to educate all physicians and site staff on how to properly conduct a
study in order to collect valid patient data in a safe, compliant, and
efficient manner.
“GCP compliance and training issues top regulators‟ concerns”
M Mathieu The Global GCP Compliance Report 2006: US, EU, and Japan,
What do Investigator Meetings
achieve?
Positives
– Relationship building with investigators and site staff
– Networking between investigators
– Sharing of recruitment strategies
– Ticks the “training box”
– Marketing and corporate image benefits
– Reward for investigators‟ staff
– Good times are had by all
What do Investigator Meetings
achieve?
Negatives
– Many investigators don‟t attend
– Those who do are travel-weary
– Many send short-contract staff instead (e.g. Residents / Fellows)
– Meetings are often held long before the study can commence
– Variable quality of presentation skills
– Competing attractions of locale (if held in Gloomsville, nobody will come)
– Enormously expensive and poor value for money.
– Few are actually trained at the end
Thanks for inviting me to the Investigator Meeting.
I never thought I’d enjoy the Louvre so much!
Я ничего не понял
I hope you feel that our Investigator Meeting was a success!
Many Investigators don't attend Meetings
Why investigators don't attend meetings:
– 35% are too busy with clinical practice
– 20% don't like travelling
– 15% believe they already understand the protocol
– 8% believe all meetings are the same
CR Focus 14, No 10, Dec 2003
When I attend an Investigator Meeting
I am polite enough to attend all the sessions
I may acquire some interesting insights into the pharmacology of the drug
I get to know some of the study staff (except the overall P.I. who is too
important)
I keep getting calls on my cell phone from the Hospital
I suffer „death by PowerPoint‟ and struggle to stay awake.
I stay up too late talking to friends in the bar the first night
I wait another four months afterwards to get my site initiated
By then I have forgotten most of the things I was taught at the meeting,
especially all the logistics stuff.
But, I was marked “Present” and I am assumed to be trained.
And I was nice to my hosts when I wrote the evaluation form.
When I attend an Investigator Meeting
Before your trial commences….
Ask yourself…
– What do site staff really know about the study?
– Do they understand the protocol?
– For how long will they remember it?
– How many members of the study site team know and understand the
protocol?
– Do all study staff (site, CRAs, Sponsor‟s team) have the same baseline
knowledge?
– How will they avoid confusing it with the other studies being simultaneously
done in the site?
Now…let me
see…
What do we do in
this visit…
In that trial …
?????
Variance Kills Power Calculations
Waist
Circumference?
?Royalty-free clipart from ClipArtOf.com
How do I do that 6-minute walk test again?
How do I do the cognitive function tests?
What draw tubes do the bloods go into?
What are the centrifuge settings for the Biobank specimens?
Where do I get the „dry ice‟?
How do I calculate the RECIST status?
What treatment option should I now follow based on RECIST?
Variance Kills Power Calculations
And be the same as ALL the other 200 sites in the study
Mistakes are Expensive
Cost of Data Queries in 5800 patient stat in trial
Number per Page of CRF = 0.5
Number per visit (6 CRF pages) = 3
Number per patient per year (4 visits) = 12
Number per patient per trial (3 year) = 36
Number per trial (1000 patients) = 36,000
Cost to correct each query = $ 190
Total Cost = $ 7,000,000
Personal data: B.M.Buckley: PROSPER Study 2003
It‟s not just the Investigators and Site
Staff about whom there may be
training Issues….
Not just Investigators and Site Staff ?
Survey of Monitors’ Competence in an Oncology Trial
– 35% of Monitors are managing 3 or more other Oncology Studies
– 40% of Monitors are managing 3 or more other Non-Oncology Studies
– 16% of Monitors in one G8 country had never worked in an oncology
study
– RECIST was a problem for the majority of Monitors
– One of the 5 CRO Leads had left the study within 3 months
– High monitor turnover - up to 35% within 9 months
Source: Firecrest Surveys; 2007.
What can we do?
Training needs to be:
– Protocol-directed
– Comprehensive
– Targeted at individual needs and deficiencies
– Individually paced
– Entertaining
– Brief 1
– Available trial-long for established as well as for new trial staff
1 Shakespeare W et al. Danish J Psychopathol. (1586) 200,156-8 .
What can we do?
Training needs to be :
– Monitored
– Evaluated
– Capable of providing certified competence as an outcome
– Responsive to staff needs as identified by measuring effectiveness
– For all study staff (site staff, monitors, Sponsor‟s clinical team etc.)
– Compulsory
Compulsory training?
Companies are often afraid to alienate or overburden investigators,
BUT
would you undertake the pre-clinical development of the compound using only
untrained staff over whom you had little control?
Investigator non-compliance complaints are increasing rapidly.
Our experience is that linking start-up payment with completion of training both
works and is acceptable to investigators.
How can we do it?
e-Learning based (obvious)
BUT
How good are commonly provided solutions:
– PowerPoints® on line?
– Web-casts?
– Webex-type lessons?
– Teleconferencing?
How can we do it?
To compete successfully for my time, you need to provide a solution which is:
– structured
– integrated
– effective
– efficient
– engaging
Can it be done?
Highly structured and integrated solution needs:
– Validated instructional design: “Tell, show, ask, do”
– Engaging, highly interactive presentations
– Just-in-time availability of training
– Tailored to individual needs
– Localized to language and culture of site
Can it be done?
Highly structured and integrated solution needs:
– Consistent message across study sites
– Consistent message throughout trial despite staff turnover
– Evaluation and certification capability
– Informative to Sponsor about site competence & enthusiasm
– Capable of guiding Sponsor remedial action
– Corrective instructions easily communicated during the trial
Brendan M Buckley M.D. D.Phil. FRCPI
Clinical Professor of Medicine and Pharmacology
University College Cork,
Ireland
Director of Medical Affairs
Firecrest Clinical Limited,
Limerick,
Ireland
Can you make a
difference?
Show me the results…..
Study type: Cardiovascular
– 15,000 patients across 1,000+ sites
– Global Study
Remit:
– Address data issues – Firecrest was only intervention
Results:
– 52% reduction in number of data queries
– Time to clean data reduced from 75 days to 35 days
Show me the results…..
Study type: Auto-immune Disorder
– Phase II - 50 site study
– 8 patient visits (incl Screening)
Remit:
– Protocol-specific training and site support tools
Results:
– Top 10 performing sites used Firecrest an average of 8.1 times per patient
– Top 10 performing sites had an average of 54% less protocol deviations
per patient
Show me the results…..
Study type: Oncology
– Phase III - 140 site study
– Global
Remit:
– RECIST training and calculator tool
Results:
– Reduction in Tumour Response calculation errors by 71%
How can you do it?
Before your trial commences…
Ask yourself…
– What do site staff really know about the study and how long will they
remember?
– How many members of the study site team know and understand the
protocol?
– Do all study staff (site, CRAs, Sponsor‟s team) have the same baseline
knowledge?
– How will they avoid confusing it with the other studies being simultaneously
done in the site?
INFORMATION is not INSTRUCTION!
Remember what sites need to know
and when they need to know it!
1. What have I got to do at this visit?
2. How do I do it?
3. Where do I report it?
Nigel Hughes BSc (Pharm)
Business Development
Firecrest Clinical Limited,
Limerick,
Ireland
Email: [email protected]
